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WO2008109518B1 - Nucleic acid compounds for inhibiting wnt gene expression and uses thereof - Google Patents

Nucleic acid compounds for inhibiting wnt gene expression and uses thereof

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Publication number
WO2008109518B1
WO2008109518B1 PCT/US2008/055649 US2008055649W WO2008109518B1 WO 2008109518 B1 WO2008109518 B1 WO 2008109518B1 US 2008055649 W US2008055649 W US 2008055649W WO 2008109518 B1 WO2008109518 B1 WO 2008109518B1
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Prior art keywords
strand
molecule
human
mdrna
nucleotides
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Ceased
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PCT/US2008/055649
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French (fr)
Other versions
WO2008109518A1 (en
Inventor
Steven C Quay
James Mcswiggen
Narendra K Vaish
Mohammad Ahmadian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Marina Biotech Inc
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MDRNA Inc
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Filing date
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Application filed by MDRNA Inc filed Critical MDRNA Inc
Priority to US12/529,532 priority Critical patent/US20100055784A1/en
Priority to EP08731244A priority patent/EP2121926A1/en
Priority to JP2009551886A priority patent/JP2010519913A/en
Priority to CA002679339A priority patent/CA2679339A1/en
Publication of WO2008109518A1 publication Critical patent/WO2008109518A1/en
Publication of WO2008109518B1 publication Critical patent/WO2008109518B1/en
Priority to US12/552,082 priority patent/US20100105134A1/en
Anticipated expiration legal-status Critical
Priority to US13/327,545 priority patent/US20130011922A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing WNT1, WNT2, or WNT3A gene expression. An mdRNA of this disclosure comprises at least three strands that combine to form at least two non-overlapping double-stranded regions separated by a nick or gap wherein one strand is complementary to a WNT1, WNT2, or WNT3A mRNA. In addition, the meroduplex may have at least one uridine is a 5-methyluridine, a nucleoside is a locked nucleic acid, or optionally other modifications, and any combination thereof. Also provided are methods of decreasing expression of a WNT1, WNT2, or WNT3A gene in a cell or in a subject to treat a WNT1, WNT2, or WNT3A-related disease.

Claims

AMENDED CLAIMS received by the International Bureau on 18 September 2008 (18.09.2008)WHAT IS CLAIMED IS:
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human Wingless-Type MMTV (Murine Mammary Tumor Virus) Integration Site Family (WNT) Member 1, WNT2, and/or WNT3A mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human WNTl mRNA as set forth in SEQ ID NO:1158, the human WNT2 mRNA as set forth in SEQ ID NO:1390, or the human WNT3A mRNA as set forth in SEQ ID NO:1615, and a second strand and a third strand that is each complementary to non-overlapping regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap.
2. The mdRNA molecule of claim 1 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
3. The mdRNA molecule of claim 1 wherein the gap comprises from 1 to 10 unpaired nucleotides.
4. The mdRNA molecule of claim 1 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
5. The mdRNA molecule of claim 1 wherein the mdRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
6. The mdRNA molecule of claim 1 wherein the mdRNA contains an overhang of one to four nucleotides on at least one 3'-end that is not part of the gap or has a blunt end at one or both ends of the mdRNA.
7. An mdRNA molecule that down regulates the expression of a human WNTl, WNT2 and/or WNT3A mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human WNTl mRNA as set forth in SEQ ID NO:1158, the human WNT2 mRNA as set forth in SEQ ID NO: 139O5 or the human WNT3A mRNA as set forth in SEQ ID NO: 1615,
85 and a second strand and a third strand that is each complementary to non-overlapping regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap, and wherein at least one pyrimidine of the mdRNA molecule is a pyrimidine nucleoside according to Formula I or II:
Figure imgf000004_0001
wherein:
R1 and R2 are each independently a -H, -OH5 -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted C1-C10 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-C10 alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡≡, or heterocyclo group,
R3 and R4 are each independently a hydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and
R and R are each independently O or S.
8. The mdRNA molecule of claim 7 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
9. The mdRNA molecule of claim 7 wherein the gap comprises from 1 to 10 unpaired nucleotides.
86
10. The mdRNA molecule of claim 7 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
11. The mdRNA molecule of claim 7 wherein at least one R2 is selected from the group consisting of 2'-0-(C1-C5) alkyl, 2'-O-methyl, 2'-OCH2OCH2CH3, 2'-OCH2CH2OCH3, 2'-0-allyl, and fluoro.
12. The mdRNA molecule of claim 7 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
13. The mdRNA molecule of claim 7 wherein the mdRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
14. The mdRNA molecule of claim 7 wherein contains an overhang of one to four nucleotides on at least one 3 '-end that is not a part of the gap or the dsRNA molecule has a blunt end on one or both ends of the mdRNA molecule.
15. An mdRNA molecule that down regulates the expression of a human WNTl, WNT2 and/or WNT3A mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human WNTl mRNA as set forth in SEQ ID NO: 1158, the human WNT2 mRNA as set forth in SEQ ID NO:1390, or the human WNT3A mRNA as set forth in SEQ ID NO:1615, and a second strand and a third strand that is each complementary to non-overlapping regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap, and wherein the double-stranded regions have a combined length of about 15 base pairs to about 40 base pairs.
16. The mdRNA molecule of claim 15 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
17. The mdRNA molecule of claim 15 wherein the gap comprises from 1 to 10 unpaired nucleotides.
87
18. The mdRNA molecule of claim 15 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human WNTl nucleic acid sequence as set forth in any one of SEQ ID NOS:1159-1389, a human WNT2 nucleic acid sequence as set forth in any one of SEQ ID NOS: 1391-1614, or a human WNT3A nucleic acid sequence as set forth in any one of SEQ ID NOS: 1616-1901.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human WNTl nucleic acid sequence as set forth in any one of SEQ ID NOS:1159-1389, a human WNT2 nucleic acid sequence as set forth in any one of SEQ ID NOS:1391-1614, or a human WNT3A nucleic acid sequence as set forth in any one of SEQ ID NOS: 1616-1901.
21. A method for reducing the expression of a human WNTl , WNT2 and/or WNT3 A gene, comprising administering an mdRNA molecule according to any one of claims 1-20 to a cell expressing a human WNTl, WNT2 and/or WNT3A gene, wherein the mdRNA molecule reduces the expression of a human WNTl, WNT2 and/or WNT3 A gene in the cell.
22. The method according to claim 21 wherein the cell is a human cell.
23. Use of an mdRNA as defined in any one of the preceding claims for the manufacture of a medicament for use in the therapy of a metabolic disease.
24. A double-stranded ribonucleic acid (dsRNA) molecule that down regulates the expression of a human Wingless-Type MMTV (Murine Mammary Tumor Virus) Integration Site Family, (WNT) Member 1, WNT2, and/or WNT3A mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to the human WNTl mRNA as set forth in SEQ ID NO: 1158, the human WNT2 mRNA as set forth in SEQ ID NO: 1390, or the human WNT3A mRNA as set forth in SEQ ID NO:1615, and a second strand that is complementary to the first strand, and wherein upon annealing of the first strand and the second strand the dsRNA has a 3' overhang and a blunt end.
88
25. The dsRNA molecule of claim 24 wherein the first strand is from 27 to 35 nucleotides in length.
26. The dsRNA molecule of claim 24 wherein the dsRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
27. The dsRNA molecule of claim 24 wherein the dsRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
28. The dsRNA molecule of claim 24 wherein the 3'-overhang has from one to four nucleotides and is on the first strand.
29. The dsRNA molecule of claim 24 wherein the dsRNA molecule has a 5'-terminal end comprising a hydroxyl or a phosphate.
30. A dsRNA molecule that down regulates the expression of a human WNTl, WNT2 and/or WNT3A mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to the human WNTl mRNA as set forth in SEQ ID NO: 1158, the human WNT2 mRNA as set forth in SEQ ID NO-.1390, or the human WNT3A mRNA as set forth in SEQ ID NO:1615, and wherein upon annealing of the first strand and the second strand the dsRNA has a 3' overhang and a blunt end, and wherein at least one pyrimidine of the dsRNA molecule comprises a pyrimidine nucleoside according to Formula I or II:
Figure imgf000007_0001
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH35 -OCH2CH2OCH3, halogen, substituted or unsubstiruted Ci-Cio alkyl, alkoxy,
89 alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-C1O alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡N, or heterocyclo group,
R3 and R4 are each independently a hydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and
R5 and R8 are each independently O or S.
31. The dsRNA molecule of claim 30 wherein the first strand is from 27 to 35 nucleotides in length.
32. The dsRNA molecule of claim 30 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
33. The dsRNA molecule of claim 30 wherein at least one R2 is selected from the group consisting of 2'-0-(C1-C5) alkyl, 2'-0-methyl, 2'-OCH2OCH2CH3, 2'-OCH2CH2OCH3, 2'-0-allyl, and 2'-fluoro.
34. The dsRNA molecule of claim 30 wherein the dsRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
35. The dsRNA molecule of claim 30 wherein the dsRNA molecule comprises at least one LNA, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
36. The dsRNA molecule of claim 30, wherein the 3'-overhang has from one to four nucleotides and is on the first strand.
37. A method for reducing the expression of a human WNTl , WNT2 and/or WNT3 A gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing the human WNTl, WNT2 and/or WNT3A
90 gene, wherein the dsRNA molecule reduces the expression of the human WNTl, WNT2 and/or WNT3 A gene in the cell.
38, The method according to claim 37 wherein the cell is a human cell.
39. Use of a dsRNA molecule as defined in any one of claims 24-38 for the manufacture of a medicament for use in the therapy of a metabolic disease.
91
PCT/US2008/055649 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting wnt gene expression and uses thereof Ceased WO2008109518A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US12/529,532 US20100055784A1 (en) 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting wnt gene expression and uses thereof
EP08731244A EP2121926A1 (en) 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting wnt gene expression and uses thereof
JP2009551886A JP2010519913A (en) 2007-03-02 2008-03-03 NUCLEIC ACID COMPOUND AND USE THEREOF FOR SUPPRESSING WNT GENE EXPRESSION
CA002679339A CA2679339A1 (en) 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting wnt gene expression and uses thereof
US12/552,082 US20100105134A1 (en) 2007-03-02 2009-09-01 Nucleic acid compounds for inhibiting gene expression and uses thereof
US13/327,545 US20130011922A1 (en) 2007-03-02 2011-12-15 Nucleic acid compounds for inhibiting gene expression and uses thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US93494007P 2007-03-02 2007-03-02
US60/934,940 2007-03-02
US93493007P 2007-03-16 2007-03-16
US60/934,930 2007-03-16
US1561107P 2007-12-20 2007-12-20
US61/015,611 2007-12-20

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PCT/US2008/055651 Continuation-In-Part WO2008109520A2 (en) 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting cxc gene expression and uses thereof
AU2009212920A Division AU2009212920A1 (en) 2007-03-02 2009-09-01 Nucleic acid compounds for inhibiting gene expression and uses thereof
US12/552,082 Continuation-In-Part US20100105134A1 (en) 2007-03-02 2009-09-01 Nucleic acid compounds for inhibiting gene expression and uses thereof

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WO2008109518A1 (en) 2008-09-12
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JP2010519913A (en) 2010-06-10
US20100055784A1 (en) 2010-03-04

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